tbuckley/cabot-search huggingface dataset:
Comprehensive profiling of clinical <scp>JAK</scp> inhibitors in myeloproliferative neoplasms
Authors: Tim Kong, LaYow Yu, Angelo B. A. Laranjeira, Daniel A. C. Fisher, Fan He, Maggie J. Cox, Stephen T. Oh
Journal: American Journal of Hematology (2023)

Abstract Small molecule inhibitors targeting JAK2 provide symptomatic benefits for myeloproliferative neoplasm (MPN) patients and are among first‐line therapeutic agents. However, despite all having potent capacity to suppress JAK–STAT signaling, they demonstrate distinct clinical profiles suggesting contributory effects in targeting other ancillary pathways. Here, we performed comprehensive profiling on four JAK2 inhibitors either FDA‐approved (ruxolitinib, fedratinib, and pacritinib) or undergoing phase 3 studies (momelotinib) to better outline mechanistic and therapeutic efficacy. Across JAK2 ‐mutant in vitro models, all four inhibitors demonstrated similar anti‐proliferative phenotypes, whereas pacritinib yielded greatest potency on suppressing colony formation in primary samples, while momelotinib exhibited unique erythroid colony formation sparing. All inhibitors reduced leukemic engraftment, disease burden, and extended survival across patient‐derived xenograft (PDX) models, with strongest effects elicited by pacritinib. Through RNA‐sequencing and gene set enrichment analyses, differential suppressive degrees of JAK–STAT and inflammatory response signatures were revealed, which we validated with signaling and cytokine suspension mass cytometry across primary samples. Lastly, we assessed the capacity of JAK2 inhibitors to modulate iron regulation, uncovering potent suppression of hepcidin and SMAD signaling by pacritinib. These comparative findings provide insight into the differential and beneficial effects of ancillary targeting beyond JAK2 and may help guide the use of specific inhibitors in personalized therapy.
Predicting deep surgical site infection in patients receiving open posterior instrumented thoracolumbar surgery: A-DOUBLE-SSI risk score – a large retrospective multicenter cohort study in China
Authors: Lei Cheng, Jiesheng Liu, Liyi Lian, Wanru Duan, Jian Guan, Kai Wang, Zhenlei Liu, Xingwen Wang, Zuowei Wang, Hao Wu, Zan Chen, Jianzhen Wang, Fengzeng Jian
Journal: International Journal of Surgery (2023)

To develop a practical prediction model to predict the risk of deep surgical site infection (SSI) in patients receiving open posterior instrumented thoracolumbar surgery.Data of 3419 patients in four hospitals from 1 January 2012 to 30 December 2021 were evaluated. The authors used clinical knowledge-driven, data-driven, and decision tree model to identify predictive variables of deep SSI. Forty-three candidate variables were collected, including 5 demographics, 29 preoperative, 5 intraoperative, and 4 postoperative variables. According to model performance and clinical practicability, the best model was chosen to develop a risk score. Internal validation was performed by using bootstrapping methods.After open posterior instrumented thoracolumbar surgery, 158 patients (4.6%) developed deep SSI. The clinical knowledge-driven model yielded 12 predictors of deep SSI, while the data-driven and decision tree model produced 11 and 6 predictors, respectively. A knowledge-driven model, which had the best C-statistics [0.81 (95% CI: 0.78-0.85)] and superior calibration, was chosen due to its favorable model performance and clinical practicality. Moreover, 12 variables were identified in the clinical knowledge-driven model, including age, BMI, diabetes, steroid use, albumin, duration of operation, blood loss, instrumented segments, powdered vancomycin administration, duration of drainage, postoperative cerebrospinal fluid leakage, and early postoperative activities. In bootstrap internal validation, the knowledge-driven model still showed optimal C-statistics (0.79, 95% CI: 0.75-0.83) and calibration. Based on these identified predictors, a risk score for deep SSI incidence was created: the A-DOUBLE-SSI (Age, D [Diabetes, Drainage], O [duration of Operation, vancOmycin], albUmin, B [BMI, Blood loss], cerebrospinal fluid Leakage, Early activities, Steroid use, and Segmental Instrumentation) risk score. Based on the A-DOUBLE-SSI score system, the incidence of deep SSI increased in a graded fashion from 1.06% (A-DOUBLE-SSIs score ≤8) to 40.6% (A-DOUBLE-SSIs score>15).The authors developed a novel and practical model, the A-DOUBLE-SSIs risk score, that integrated easily accessible demographics, preoperative, intraoperative, and postoperative variables and could be used to predict individual risk of deep SSI in patients receiving open posterior instrumented thoracolumbar surgery.
A Mitochondria‐Targeted Ferroptosis Inducer Activated by Glutathione‐Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics
Authors: Hongbo Gan, Xie Huang, Xi Luo, Jinlin Li, Banghui Mo, Lizhi Cheng, Qiuxia Shu, Zaizhi Du, Hong Tang, Wei Sun, Liting Wang, Shenglin Luo, Songtao Yu
Journal: Advanced Healthcare Materials (2023)

Ferroptosis is a new type of iron-dependent programmed cell death characterized by glutathione (GSH) depletion, selenoprotein glutathione peroxidase 4 (GPX4) inactivation, and lipid peroxides accumulation. Mitochondria, as the main source of intracellular energy supply and reactive oxygen species (ROS) generation, play a central role in oxidative phosphorylation and redox homeostasis. Therefore, targeting cancer-cell mitochondria and attacking redox homeostasis is expected to induce robust ferroptosis-mediated anticancer effects. In this work, a theranostic ferroptosis inducer (IR780-SPhF), which can simultaneously achieve the imaging and therapy of triple-negative breast cancer (TNBC) by targeting mitochondria is presented. It is developed from a mitochondria-targeting small molecule (IR780) with cancer-preferential accumulation, enabling it to react with GSH by nucleophilic substitution, resulting in mitochondrial GSH depletion and redox imbalance. More interestingly, IR780-SPhF exhibits GSH-responsive near-infrared fluorescence emission and photoacoustic imaging characteristics, further facilitating diagnosis and treatment with real-time monitoring of TNBC with a highly elevated GSH level. Both in vitro and in vivo results demonstrate that IR780-SPhF exhibits potent anticancer effect, which is significantly stronger than cyclophosphamide, a classic drug commonly recommended for TNBC patients in clinic. Hence, the reported mitochondria-targeted ferroptosis inducer may represent a promising candidate and a prospective strategy for efficient cancer treatment.
Quantification of vessel separation using the carotid-jugular angle to predict the nerve origin of neck peripheral nerve sheath tumours: a pooled analysis of cases from the literature and a single-center cohort
Authors: Chia-En Wong, Chi-Chen Huang, Ming-Tsung Chuang, Po-Hsuan Lee, Liang-Yi Chen, Hao-Hsiang Hsu, Chih-Yuan Huang, Liang-Chao Wang, Jung-Shun Lee
Journal: International Journal of Surgery (2023)

Postoperative nerve palsy is a major complication following resection of neck peripheral nerve sheath tumours (PNSTs). Accurate preoperative identification of the nerve origin (NO) can improve surgical outcomes and patient counselling.This study was a retrospective cohort and quantitative analysis of the literature. The authors introduced a parameter, the carotid-jugular angle (CJA), to differentiate the NO. A literature review of neck PNST cases from 2010 to 2022 was conducted. The CJA was measured from eligible imaging data, and quantitative analysis was performed to evaluate the ability of the CJA to predict the NO. External validation was performed using a single-centre cohort from 2008 to 2021.In total, 17 patients from our single-centre cohort and 88 patients from the literature were analyzed. Among them, 53, 45, and 7 patients had sympathetic, vagus, and cervical nerve PNSTs, respectively. Vagus nerve tumours had the largest CJA, followed by sympathetic tumours, whereas cervical nerve tumours had the smallest CJA ( P <0.001). Multivariate logistic regression identified a larger CJA as a predictor of vagus NO ( P <0.001), and receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.907 (0.831-0.951) for the CJA to predict vagus NO ( P <0.001). External validation showed an AUC of 0.928 (0.727-0.988) ( P <0.001). Compared with the AUC of the previously proposed qualitative method (AUC=0.764, 0.673-0.839), that of the CJA was greater ( P =0.011). The cut-off value identified to predict vagus NO was greater than or equal to 100°. Receiver operating characteristic analysis showed an AUC of 0.909 (0.837-0.956) for the CJA to predict cervical NO ( P <0.001), with a cut-off value less than 38.5°.A CJA greater than or equal to 100° predicted a vagus NO and a CJA less than 100° predicted a non-vagus NO. Moreover, a CJA less than 38.5 was associated with an increased likelihood of cervical NO.
Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production
Authors: Shyamala Thirunavukkarasu, Mushtaq Ahmed, Bruce A. Rosa, Mark Boothby, Sung Hoon Cho, Javier Rangel-Moreno, Stanley K. Mbandi, Valérie Schreiber, Ananya Gupta, Joaquin Zuniga, Makedonka Mitreva, Deepak Kaushal, Thomas J. Scriba, Shabaana A. Khader
Journal: Journal of Clinical Investigation (2023)

The ADP ribosyltransferases (PARPs 1–17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). Although PARP9 mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme was upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cyclic GMP–AMP synthase (cGAS) expression, and type I IFN production during TB. Thus, Parp9-deficient mice were susceptible to Mycobacterium tuberculosis infection and exhibited increased TB disease, cGAS and 2′3′-cyclic GMP-AMP (cGAMP) expression, and type I IFN production, along with upregulation of complement and coagulation pathways. Enhanced M. tuberculosis susceptibility is type I IFN dependent, as blockade of IFN α receptor (IFNAR) signaling reversed the enhanced susceptibility of Parp9–/– mice. Thus, in sharp contrast to PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB.
Prognostic factors for acute vertebrobasilar artery occlusion-reperfusion: a multicenter retrospective cohort study
Authors: Zhi-Xin Huang, Jianguo Lin, Yunfei Han, Shizhan Li, Yongkun Li, Qiankun Cai, Yingyi Dai
Journal: International Journal of Surgery (2023)

This study aimed to analyze the long-term prognostic factors in acute vertebrobasilar artery occlusion (VBAO) patients treated with endovascular treatment (EVT).This study was performed using the acute posterior circulation ischemic stroke registry database from 21 stroke centers in 18 cities in China and retrospectively included consecutive patients aged 18 years or older with an acute, symptomatic, radiologically confirmed VBAO who were treated with EVT between December 2015 and December 2018. Favorable clinical outcomes were evaluated by machine-learning methods. A clinical signature was constructed in the training cohort using the least absolute shrinkage and selection operator regression and was validated in the validation cohort.From 28 potential factors, 7 variables were independent prognostic factors and were included in the model: Modified Thrombolysis in Cerebral Infarction (M) [odds ratio (OR): 2.900; 95% confidence interval [CI]: 1.566-5.370], age (A) (OR, 0.977; 95% CI: 0.961-0.993), National Institutes of Health Stroke Scale (N) (13-27 vs. ≤12: OR, 0.491; 95% CI: 0.275-0.876; ≥28 vs. ≤12: OR, 0.148; 95% CI: 0.076-0.289), atrial fibrillation (A) (OR, 2.383; 95% CI: 1.444-3.933), Glasgow Coma Scale (G) (OR, 2.339; 95% CI: 1.383-3.957), endovascular stent-retriever thrombectomy (E) (stent-retriever vs. aspiration: OR, 0.375; 95% CI: 0.156-0.902), and estimated time of onset of the occlusion to groin puncture (Time) (OR, 0.950; 95% CI: 0.909-0.993) (abbreviated as MANAGE Time). In the internal validation set, this model was well calibrated with good discrimination [C-index (95% CI)=0.790 (0.755-0.826)]. A calculator based on the model can be found online ( http://ody-wong.shinyapps.io/1yearFCO/ ).Our results indicate that optimizing for EVT, along with specific risk stratification, may improve long-term prognosis. However, a larger prospective study is needed to confirm the findings.
Rare Disease, Advocacy and Justice: Intersecting Disparities in Research and Clinical Care
Authors: Meghan C. Halley, Colin M. E. Halverson, Holly K. Tabor, Aaron J. Goldenberg
Journal: The American Journal of Bioethics (2023)

Rare genetic diseases collectively impact millions of individuals in the United States. These patients and their families share many challenges including delayed diagnosis, lack of knowledgeable providers, and limited economic incentives to develop new therapies for small patient groups. As such, rare disease patients and families often must rely on advocacy, including both self-advocacy to access clinical care and public advocacy to advance research. However, these demands raise serious concerns for equity, as both care and research for a given disease can depend on the education, financial resources, and social capital available to the patients in a given community. In this article, we utilize three case examples to illustrate ethical challenges at the intersection of rare diseases, advocacy and justice, including how reliance on advocacy in rare disease may drive unintended consequences for equity. We conclude with a discussion of opportunities for diverse stakeholders to begin to address these challenges.
The Clinical Impact of Electronic <scp>Patient‐Reported</scp> Outcome Measures in the Remote Monitoring of Inflammatory Arthritis: A Systematic Review and Meta‐analysis
Authors: Nikita Arumalla, Chun K. D. Chan, Mark Gibson, Yik L. Man, Maryam A. Adas, Sam Norton, James B. Galloway, Toby Garrood
Journal: Arthritis & Rheumatology (2023)

Objective The inflammatory arthritides (IAs) make up a significant proportion of conditions followed up in rheumatology clinics. These patients require regular monitoring, but this is increasingly difficult with rising patient numbers and demand on clinics. Our objective is to evaluate the clinical impact of electronic patient‐reported outcome measures (ePROMs) as a digital remote‐monitoring intervention on disease activity, treatment decisions, and health care resource use in patients with IA. Methods Five databases (MEDLINE, Embase, PubMed, Cochrane Library, and Web of Science) were searched, with randomized controlled trials and (nonrandomized) controlled clinical trials included, and meta‐analysis and forest plots conducted for each outcome. Risk of bias was assessed using the Risk of Bias‐2 tool and Risk of Bias in Nonrandomized Studies of Interventions. Results Eight studies were included with a total of 4,473 patients, with seven studies assessing patients with rheumatoid arthritis. Compared with control, the disease activity in the ePROM group was lower (standardized mean difference [SMD] −0.15; 95% confidence interval [CI] −0.27 to −0.03) and rates of remission/low disease activity were higher (odds ratio1.65; 95% CI 1.02–2.68), but five of eight studies provided additional combined interventions (e.g., disease education). Fewer face to face visits were needed in the remote ePROM group (SMD −0.93; 95% CI −2.14–0.28). Conclusion Most studies were at high risk of bias with significant heterogeneity in design, but our results suggest there is an advantage in using ePROM monitoring in patients with IAs, with the potential for reduction in health care resource use without detrimental impact in disease outcomes.
Reply: People living with HIV and NAFLD and updated guidance on NAFLD screening
Authors: Mary E. Rinella, Norah Terrault, Brent Neuschwander-Tetri, Rohit Loomba
Journal: Hepatology (2023)

1The University of Chicago 2University of Southern California, AASLD President Correspondence Mary E. Rinella, MD, University of Chicago Biological Sciences Division. Email: [email protected]
Automated diagnosis and management of follicular thyroid nodules based on the devised small-dataset interpretable foreground optimization network deep learning: a multicenter diagnostic study
Authors: Zheyu Yang, Siqiong Yao, Yu Heng, Pengcheng Shen, Tian Lv, Siqi Feng, Lei Tao, Weituo Zhang, Weihua Qiu, Hui Lu, Wei Cai
Journal: International Journal of Surgery (2023)

Currently, follicular thyroid carcinoma (FTC) has a relatively low incidence with a lack of effective preoperative diagnostic means. To reduce the need for invasive diagnostic procedures and to address information deficiencies inherent in a small dataset, we utilized interpretable foreground optimization network deep learning to develop a reliable preoperative FTC detection system.In this study, a deep learning model (FThyNet) was established using preoperative ultrasound images. Data on patients in the training and internal validation cohort ( n =432) were obtained from Ruijin Hospital, China. Data on patients in the external validation cohort ( n =71) were obtained from four other clinical centers. We evaluated the predictive performance of FThyNet and its ability to generalize across multiple external centers and compared the results yielded with assessments from physicians directly predicting FTC outcomes. In addition, the influence of texture information around the nodule edge on the prediction results was evaluated.FThyNet had a consistently high accuracy in predicting FTC with an area under the receiver operating characteristic curve (AUC) of 89.0% [95% CI 87.0-90.9]. Particularly, the AUC for grossly invasive FTC reached 90.3%, which was significantly higher than that of the radiologists (56.1% [95% CI 51.8-60.3]). The parametric visualization study found that those nodules with blurred edges and relatively distorted surrounding textures were more likely to have FTC. Furthermore, edge texture information played an important role in FTC prediction with an AUC of 68.3% [95% CI 61.5-75.5], and highly invasive malignancies had the highest texture complexity.FThyNet could effectively predict FTC, provide explanations consistent with pathological knowledge, and improve clinical understanding of the disease.
Promoting Equality in the Governance of Heritable Human Genome Editing through Ubuntu: Reflecting on a South African Public Engagement Study
Authors: Bonginkosi Shozi, Donrich Thaldar
Journal: The American Journal of Bioethics (2023)

In a recent public engagement study on heritable human genome editing (HHGE) conducted among South Africans, participants approved of using HHGE for serious health conditions-viewing it as a means of bringing about valuable social goods-and proposed that the government should actively invest resources to ensure everyone has equal access to the technology for these purposes. This position was animated by the view that future generations have a claim to these social goods, and this entitlement justified making HHGE available in the present. This claim can be ethically justified in the Ubuntu ethic (deriving from South Africa) as it (a) emphasizes the interests of the community, and (b) espouses a metaphysical conception of the community that transcends the present generation and includes past and future generations. On this basis, a compelling claim can be made on behalf of prospective persons in favor of equal access to HHGE.
<i>Notes from the Field:</i> Legionnaires Disease in a U.S. Traveler After Staying in a Private Vacation Rental House in the U.S. Virgin Islands — United States, February 2022
Authors: Valerie V. Mac, Katie Labgold, Heidi L. Moline, Jessica C. Smith, Jamaal Carroll, Nakia Clemmons, Chris Edens, Brett Ellis, Cosme Harrison, Kelley C. Henderson, Maliha K. Ishaq, Natalia A. Kozak-Muiznieks, Jasen Kunz, Marlon Lawrence, Claressa E. Lucas, Heather L. Walker, Melisa J. Willby, Esther M. Ellis
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

On February 1, 2022, the U.S. Virgin Islands (USVI) Department of Health (VIDOH) was notified of a confirmed case of Legionnaires disease in an adult U.S. resident (Figure).The patient, a man aged 55 years, returned to his U.S. state of residence from leisure travel in USVI on January 22 and developed a cough, shortness of breath, and fatigue on January 23.On January 29, he was hospitalized for shortness of breath and received a positive SARS-CoV-2 test result at admission.The combination of the patient's symptoms and recent travel history prompted administration of a urinary antigen test (UAT) for Legionnaires disease specific to Legionella pneumophila serogroup 1 (Lp1); a positive result was returned on January 31.Inpatient treatment administered for COVID-19 pneumonia and Legionnaires disease included remdesivir, oral levofloxacin, oral and intravenous steroid therapy, and as-needed use of a bronchodilator inhaler and an expectorant.Remdesivir was discontinued during inpatient
Magnetic resonance elastography-based prediction model for hepatic decompensation in NAFLD: A multicenter cohort study
Authors: Beom Kyung Kim, Jaclyn Bergstrom, Rohan Loomba, Nobuharu Tamaki, Namiki Izumi, Atsushi Nakajima, Ramazan Idilman, Mesut Gumussoy, Digdem K. Oz, Ayse Erden, Emily Truong, Ju Dong Yang, Mazen Noureddin, Alina M. Allen, Rohit Loomba, Veeral Ajmera
Journal: Hepatology (2023)

Background and Aims: Magnetic resonance elastography (MRE) is an accurate, continuous biomarker of liver fibrosis; however, the optimal combination with clinical factors to predict the risk of incident hepatic decompensation is unknown. Therefore, we aimed to develop and validate an MRE-based prediction model for hepatic decompensation for patients with NAFLD. Approach and Results: This international multicenter cohort study included participants with NAFLD undergoing MRE from 6 hospitals. A total of 1254 participants were randomly assigned as training (n = 627) and validation (n = 627) cohorts. The primary end point was hepatic decompensation, defined as the first occurrence of variceal hemorrhage, ascites, or HE. Covariates associated with hepatic decompensation on Cox-regression were combined with MRE to construct a risk prediction model in the training cohort and then tested in the validation cohort. The median (IQR) age and MRE values were 61 (18) years and 3.5 (2.5) kPa in the training cohort and 60 (20) years and 3.4 (2.5) kPa in the validation cohort, respectively. The MRE-based multivariable model that included age, MRE, albumin, aspartate aminotransferase, and platelets had excellent discrimination for the 3- and 5-year risk of hepatic decompensation (c-statistic 0.912 and 0.891, respectively) in the training cohort. The diagnostic accuracy remained consistent in the validation cohort with a c-statistic of 0.871 and 0.876 for hepatic decompensation at 3 and 5 years, respectively, and was superior to Fibrosis-4 in both cohorts ( p &lt; 0.05). Conclusions: An MRE-based prediction model allows for accurate prediction of hepatic decompensation and assists in the risk stratification of patients with NAFLD.